Jagdish A. Desai

Enantioselective synthesis of the optical isomers of broad-spectrum orally active antifungal azoles, Sch 42538 and Sch 45012

Abstract Sharpless-Katsuki asymmetric epoxidation of 1 provided the (R)-(+)- and (S)-(−) epoxy alcohols 2R and 2S as key intermediates towards all six stereoisomers of the title compounds. Sch 50001 and Sch 50002 (the “eutomers” of Sch 45012) are novel antifungals which display greatly improved oral activity over itraconazole and saperconazole.

Sch 51048, a novel broad-spectrum orally active antifungal agent: Synthesis and preliminary structure-activity profile

Abstract Synthesis of Sch 51048, a novel orally active azole antifungal, is described. Based on its superior oral efficacy over other available agents against a variety of fungal pathogens in normal and immunocompromised animal infection models, Sch 51048 is a subject for possible clinical evaluation.

Aqueous Diels-Alder reactions of electron deficient 2-arylfurans: a highly stereoselective route to 2,2,5-trisubstituted tetrahydrofurans towards a novel class of orally active azole antifungals

Aqueous Diels-Alder reactions 1 of halogenated 2-arylfurans with acetylenedicarboxylates made available previously inaccessible adducts (2, 2a, 7, and 8) which were successfully elaborated in a general stereocontrolled route to the title compounds

Discovery of C-imidazole azaheptapyridine FPT inhibitors.

The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.

TOTAL SYNTHESIS OF THE ANTIFUNGAL CYCLIC DEPSIPEPTIDES SCH 57697 AND AUREOBASIDIN A

Abstract A novel cyclic depsinonapeptide antifungal 1a (Sch 57697) and its isomer 1b were synthesized by a fragment coupling approach and this methodology was applied to the total synthesis of the natural product aureobasidin A. Synthetic strategies for coupling of N-methyl amino acids with minimal racemization are discussed. Biological evaluation of isomers 1a and 1b demonstrated the importance of chirality at the β-hydroxy-N-methylvaline (OHMeVal) position.

A convenient degradation of polyoxin D to uracil polyoxin C: access to key intermediates and synthesis of antifungal α-aminoacyl derivatives of UPOC

Abstract A convenient degradation of readily available polyoxin D under Edman conditions gave carboxyuracil polyoxin C 3 in high yield. Decarboxylation to uracil polyoxin C 5 (UPOC) and ring contraction to imidazolone compound 8 , gav important nikkomycin Z and X intermediates respectively. Syntheses of new polyoxin/nikkomycin analogs 12 – 27 , some with excellent chitin synthetase inhibition and Candida albicans whole cell activity are described. The importance of β-methyl substituted amino acid side chains for whole cell activity is highlighted.

Synthesis of 14-α-aminomethyl substituted lanosterol derivatives; inhibitors of fungal ergosterol biosynthesis

Several 14-α-aminomethyl-substituted lanosterol derivatives have been synthesized involving a complete Δ7,8to Δ8,9isomerization; these compounds are inhibitors of fungal ergosterol biosynthesis and are active against intact Candida and dermatophyte strains.

Synthesis of 5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-N-cyanoguanidine derivatives as inhibitors of ras farnesyl protein transferase.

A series of novel N-cyanoguanidine tricyclic farnesyl protein transferase (FPT) inhibitors was prepared. Replacement of a piperidine amide-group with a N-cyanoguanidine functionality increased FPT activity. X-ray crystal structure determination of 42 complexed with FPT revealed differences in the interactions of the amide and N-cyanoguanidine groups with the protein.